Sporadic Alzheimer?s disease (AD) is the most common form of dementia and it has no cure or effective treatment. The vast majority of therapies are based on the amyloid hypothesis, which postulates that amyloid A? accumulation in the brain is the key disease initiator. Accordingly, those therapies have focused on removing excess A? but, unfortunately, they have failed to produce clinical improvements. It is now evident that AD is a heterogeneous disease with likely several contributing pathogenic factors, a fact that hampers both our understanding of the disease and the design of evidence-based therapies. Of those factors, cholesterol dysregulation is prominent, being linked to at least 20% of the population at risk of developing dementia. This specific at-risk population would benefit from our understanding of the underlying pathogenic mechanisms linked to cholesterol dysregulation. In that respect, one key mechanism by which cholesterol dysregulation is involved in AD pathogenesis is through the accumulation of its oxidized metabolite 27-hydroxycholesterol (27OHC). Our laboratory has unveiled a novel protective mechanism against 27OHC cytotoxicity. We have shown that, in vitro, the intracellular domain of the amyloid precursor protein, AICD, drives a neuroprotective hormetic response against 27OHC through the upregulation of the oxysterol stress responder RTKN2 to optimize neuroprotection. This response was deficient in autopsy brain samples from AD patients and in brains of mice fed a long-term Western diet, a significant risk factor for AD that increases 27OHC in the brain. Thus, our data show that AICD-driven hormesis against 27OHC occurs in vitro and suggest that its activation could be implicated in supporting brain homeostasis and maintaining cognitive function. Accordingly, our long-term goal is to understand the hormetic mechanisms in the brain against 27OHC to ultimately optimize them for therapeutic purposes. The overall objective of this particular proposal is to demonstrate that hormesis against 27OHC occurs in the brain as a mechanism to optimize synaptic plasticity and cognitive function. Supported by strong data, our central hypothesis is that incremental exposure to dietary cholesterol, through the accumulation of 27OHC, will elicit a hormetic-response window in the mouse brain, measurable by changes in AICD-driven RTKN2 expression, hippocampal synaptic plasticity and cognitive function. We will test our hypothesis with the following Specific Aim: Measure the changes in AICD-driven RTKN2 expression, hippocampal synaptic plasticity and cognition in mice in response to increasing amounts of cholesterol in the diet. We will use sterol 27-hydroxylase-null mice, which do not generate 27OHC, and control mice, fed a standard or 0.06%, 0.125%, 0.25%, 0.375% and 0.5% cholesterol- rich diets, to measure AICD-driven RTKN2 expression, evaluate synaptic plasticity in organotypic hippocampal slices and assess a range of behavioral tasks widely used to characterize mouse models of AD. Our approach is innovative because it describes a novel neuroprotective mechanism against a known risk factor for AD and its contribution is significant because optimization of that mechanism will provide evidence-based therapy targets.